Compounds for use in weight loss and appetite suppression in humans

ABSTRACT

Phenolic compounds with a phenolic molecule to which are covalently linked an oxygen-containing group, a nitrogen or another oxygen containing group, and a C 1 -C 4  alkoxy group, obtainable from monocotyledonous plants, or by chemical synthesis, have been found to act as weight loss agents, appetite suppressants, mood enhancers and adjunctive therapy for arthritis, sleep apnea, fibromyalgia, diabetes and hyperglycemia. Additional chemical compounds of the present invention may include benzoxazinoids-cyclic hydroxyamic acids, lactams, and corresponding glucosides, which may serve as precursors to phenolic compounds. The phenolic compounds and precursors of phenolic compounds of the present invention, at concentrations suitable for human therapeutic use, may be obtained from monocotyledonous plants such as corn in their early growth states which are timely harvested for optimum yield.

1. RELATED APPLICATION

This divisional application claims the benefit of U.S. patentapplication Ser. No. 10/718,232, filed Nov. 20, 2003, which claimspriority to U.S. patent application Ser. No. 09/834,592, filed Apr. 13,2001, and entitled “NOVEL COMPOUNDS FOR USE AS ANTIDEPRESSANTS,APHRODISIACS AND ADJUNCTIVE THERAPIES IN HUMANS”, now issued as U.S.Pat. No. 6,667,308 , which claims the benefit of U.S. provisional patentapplication Ser. No. 60/196,829, filed Apr. 13, 2000, and entitled“ANTIDEPRESSANT, APHRODISIAC, WEIGHT-LOSS AIDE, THERAPY FOR QUFITINGNICOTINE OR ADDICTIVE DRUGS AND TREATMENT OF BETITERING REPRODUCTION INHUMANS”, which are incorporated herein by reference.

BACKGROUND

1. Field of the Invention

This invention relates to compositions and methods to induce weightloss, appetite suppression and as adjunctive therapies for fibromyalgia,sleep apnea, diabetes, hyperglycemia and arthritis and moreparticularly, to novel compositions of phenolic and indoleamine-likecompounds which are obtainable in concentrations and amounts suitablefor human use from certain botanicals or from chemical synthesis,together with methods for using, producing and harvesting same.

2. The Background Art

An estimated 35-40 million living Americans will suffer major depressiveepisodes, and many more will experience lesser bouts. Of theapproximately 17.5 million Americans with ongoing depressions, about 9.2million are at a clinically debilitating level. Clinical depression ischaracterized by a list of symptoms that last over a long time span. Itis a serious problem that is usually or initially caused by outsidestressors. As stresses escalate or persist, a chemical imbalance canresult. Clinical depression can be very debilitating both physically andmentally and even lead to death by means of suicide. However, lostproductivity and relationship problems are also consequences of lesserdepressions. At present, antidepressant medications are the cornerstonesof treating depression, especially those that are at least moderatelysevere. Although depressed people tend to improve when treated withantidepressants, many do not respond to the first one. Such individualsmay eventually benefit from a different antidepressant or a combinationof antidepressants.

Sexual dysfunction is a pervasive disorder. In the overall population,43 percent of women and 31 percent of men between the ages of 18 and 59repeatedly experience it. Sexual dysfunction includes lacking interestin sex, problems with arousal, not enjoying sex, and anxiety aboutsexual performance. Indeed, feeling good in general has significantimpact on sexual function, with those people unhappy or depressed morelikely to experience difficulties. Arousal problems affect over 20million American males, about two in 10 adult men, with suchdifficulties often associated with or accompanied by some sort ofdepression. Meanwhile, prescription antidepressants actually exacerbatethe situation, since a frequent side effect of their use is sexualdysfunction. In fact, sexual response diminishes in up to 75% ofprescription antidepressant users.

There is a need for treatments to reduce depression or otherwise bettermood with an accompanying enhancement of sexual response or desire, orat least no sexual dysfunction.

Prior work on the compounds of the invention has solely been on6-methoxy-2,3-benzoxazolinone (6-MBOA). Its role in strengthening theresistance of monocotyledonous plants against a wide range of insectpests has been much studied. 6-MBOA and its chemical precursors alsohave allelopathic properties that inhibit root and shoot growth incompeting species. Furthermore, it has antimicrobial properties. 6-MBOAappears constitutively during early stages of growth, localized in thosetissues most exposed to microbial and insect attack.

It had been long suspected that compounds in plants affect the seasonalreproductive output of wild rodents. In 1981, 6-MBOA became the firstnaturally occurring compound in a plant verified as impacting seasonalreproductive cycling. Since then, a substantial body of work hasaccumulated on 6-MBOA as an initiator of seasonal breeding and aneffector of population size for many rodents and a few birds. Compoundsrelated to and possibly co-occurring with 6-MBOA remain unexplored inthis regard.

Excessive weight (i.e., overweight) and obesity are part of the mostrapidly growing public health concerns facing the world today. By theend of the 1980s, nearly one-fourth of Americans were overweight (a BodyMass Index (BMI) greater than 25, calculated as weight inkilograms/height in meters squared; Calle et al., “Body mass index andmortality in a prospective cohort of US adults”, New England Journal ofMedicine 341:1097-1105, 1999) or obese (excess body weight more than 20percent above average for height, bone structure and age, or a BMIexceeding 30). The number of overweight children has nearly tripled overthe previous 20 years; and, the prevalence and incidence of type 2diabetes, a disease for which obesity is a major factor, in adolescentshas significantly increased over the same time. By 1999, aboutthirty-six percent (36%) of the total population, or more than97,000,000 adults, may be considered overweight. Currently, it has beenestimated that about sixty percent (60%) of American are overweight andabout thirty percent (30%) of Americans may be considered obese.

Obesity has a similar epidemic pattern in Europe, and in 2002 it wasestimated that more than 200 million people (about thirty-three percent(33%)) of the population could be considered overweight. In manyEuropean countries more than fifty percent (50%) of adults are nowoverweight, nearly triple the level prior to 1980. Germany has the mostoverweight men in Europe, with an incidence of seventy-one percent(71%). The United Kingdom is not far behind Germany with excess weightin more than sixty percent (60%) of the adult population.

Overweight and obesity are commonly associated with other serious healthconditions. These conditions may be causes of increased morbidity inoverweight and obese individuals. These serious health conditions andobesity are often referred to as being “co-morbid.” Being overweight isknown to increase the risk of dying from many conditions, including 4 ofthe 10 leading causes of death: coronary heart disease, cancer, strokeand type 2 diabetes. Some epidemiological information suggests increasesin mortality tend to parallel increases in body weight. In the UnitedStates, being overweight has become the second leading cause ofpreventable, premature death, with the associated annual loss of lifeexceeding 2,800,000 people (Allison et al., “Annual deaths attributableto obesity in the United States”, Journal of the American MedicalAssociation 282:1530-1538, 1999).

Excessive weight and/or obesity may be due to uncontrollable and/orcontrollable factors. Uncontrollable factors may include heredity (i.e.,genetics) and metabolic disorders. Controllable factors may includeenvironment, physical inactivity, psychological circumstances, and pooreating habits established in childhood. Poor eating habits may includeexcessive intake as well as poor selection of foods with nutritionalvalue. The controllable factors are often more responsible for thedevelopment of overweight and obesity.

Therapeutic approaches to overweight and obesity have includededucational, physical, psychological and pharmacological modalities.Educational efforts have focused on informing individuals about caloricintake and making proper nutritional selections. Physical approacheshave emphasized increasing physical activity in an effort to increasemetabolism. Psychological approaches have focused on controllingappetite, manipulating mood and improving sense of well-being.Pharmacological approaches may include drugs and other agents tosuppress appetite and/or increase cellular metabolism. There are a broadrange of opinions as to how successful these therapeutic approaches havebeen either individually or collectively, but nevertheless, incidenceand prevalence of overweight and obesity continue to increase.Regardless of cause, there is obvious need for treatments that caninduce or otherwise promote weight loss.

Medications prescribed for losing weight often suppress appetite by wayof mood enhancing attributes (Halpern et al., “Treatment of obesity. Anupdate on anti-obesity medications”, Obesity Reviews 4:25-42, 2003) andmay include, beta-phenethylamine derivatives (fenfluramine, phentermine,phendimetrazine, diethylpropion, and sibutramine); tricyclic derivatives(mazindol); a naftilamine derivative (sertraline); phenylpropanolaminederivatives (ephedrine, phenylpropanolamine); and a phenylpropanolamineoxytrifluorphenyl derivative (fluoxetine).

Ethnobotanists, pharmacognosists and medicinal chemists are constantlyin search of new compounds from plant materials that have mood enhancingproperties and possible therapeutic roles in weight loss. It had beenlong suspected that compounds in some plants effect the mood of wildrodents. These effects are sometimes examined by observing seasonalreproductive output. In 1981, 6-methoxy-2,3-benzoxazolinone (6-MBOA)became the first naturally occurring compound in a plant verified asimpacting seasonal reproductive cycling. 6-MBOA may be found in varyingconcentrations in monocotyldenous plants. Since its discovery, asubstantial body of work has accumulated on 6-MBOA as an initiator ofseasonal breeding and an effector of population size for many rodentsand a few birds. 6-MBOA is passed from adult females to offspring duringgestation and lactation, with increased growth and larger gonads in therecipient young. Juveniles rely on the interaction of maternalphotoperiod history and 6-MBOA to time the onset of growth and puberty.Adults fed a diet containing 6-MBOA produce more female progeny. When6-MBOA is fed to pregnant females, gonadal development in the maleoffspring is enhanced.

For rodents, the inhibitory effects of melatonin on growth andreproduction are blocked partially by 6-MBOA (Gower et al.,“Reproductive responses of male Microtus montanus to photoperiod,melatonin, and 6-MBOA”, Journal of Pineal Research, 8: 297-312, 1990).6-MBOA may obstruct melatonin at the melatonin receptors or actindependently to check melatonin action (Sweat et al., “Uterotropic6-methoxybenzoxazolinone is an adrenergic agonist and melatonin analog,Molecular and Cellular Endocrinology, 57:131-138, 1988).

The high melatonin levels induced by 6-MBOA may cause desensitization ofmelatonin receptors (Daya et al., “Effect of 6-methoxy-2-benzoxazolinoneon the activities of rat pineal N-acetyltransferase andhydroxyindole-O-methyltransferase and on melatonin production”, Journalof Pineal Research, 8:57-66, 1990), but not for all rodents (Anderson etal., “Effects of melatonin and 6-methoxybenzoxazolinone on photoperiodiccontrol of testis size in adult male golden hamsters”, Journal of PinealResearch, 5:351-65, 1988).

This compound stimulates rather than inhibits melatonin biosynthesis anddoes not prevent stimulation of melatonin synthesis by norepinephrine(Yuwiler et al., “Effects of 6-methoxy-2-benzoxazolinone on the pinealmelatonin generating system. J. Pharmacol. Exp. Ther. 233:45-50, 1985).6-MBOA acts at both the alpha- (α-) and beta- (β-) adrenergic receptors(Daya et al., “Effect of 6-methoxy-2-benzoxazolinone on the activitiesof rat pineal N-acetyltransferase and hydroxyindole-O-methyltransferaseand on melatonin production”, Journal of Pineal Research, 8:57-66,1990), and stimulates adenylcyclase activity in the pineal, hypothalmusand pituitary glands (Sweat et al., “Uterotropic6-methoxybenzoxazolinone is an adrenergic agonist and melatonin analog,Molecular and Cellular Endocrinology, 57:131-138, 1988).

Certain responses to 6-MBOA, like uterine hypertrophy, can be duplicatedwith estrogen, but 6-MBOA is not an estrogenic compound (Gower,“Endocrine effects of the naturally occurring reproductive stimulant,6-methoxybenzoxazolinone”, Ph.D. Thesis, University of Utah, Salt LakeCity, Utah, 1990). Also, 6-MBOA increases the rate of synthesis offollicle stimulating hormone (Butterstein et al., “The plant metabolite6-methoxybenzoxazolinone interacts with follicle-stimulating hormone toenhance ovarian growth”, Biology of Reproduction, 39:465-71, 1988) andpituitary prolactin (Vaughan et al., “Hormonal consequences ofsubcutaneous 6-methoxy-2-benzoxazolinone pellets or injections inprepubertal male and female rats”, Journal of Reproduction andFertility, 83:859-66, 1988).

Hypothalamic luteinizing hormone-releasing hormone contents andpituitary gland weights are greater for at least one rodent speciesimplanted with capsules containing 6-MBOA (Urbanski et al., “Influenceof photoperiod and 6-methoxybenzoxazolinone on the reproductive axis ofinbred LSH/Ss Lak male hamsters. Journal of Reproduction and Fertility,90:157-163, 1990). The above studies cumulatively point to 6-MBOA actingin an area of the brain, which may be referred to as the pinealhypothalamic pituitary axis (PHPA), possibly as a melatonin agonist andat the α- and β-adrenergic receptors in its own right. The inventorsrecognized that 6-MBOA and the indoleamine, melatonin, share astructural similarity. However, melatonin exacerbates symptoms ofdysphoria in depressed people. 6-MBOA, as a melatonin agonist, couldprove contrary in this regard and actually improve mood. Yet, theinventors are not aware of any prior art that has explored or suggestedthe use of 6-MBOA and related compounds as having psychotropic effectsin humans, particularly with respect to depression or mood.

An object of the invention is to develop therapies for depression andsexual dysfunction entailing use of compounds belonging to relatedchemical families, of which 6-MBOA is a member. Pursuant to this end, afurther object is to develop methods for getting said compounds fromplant and animal sources in amounts suitable for human therapeutic use.

While past research by those skilled in the art has attempted toisolate, identify and characterize new plant compounds with moodstimulating properties, 6-MBOA has heretofore previously not beenidentified or evaluated for mood elevation leading to appetitesuppression and weight loss. Therefore, as readily appreciated by thoseskilled in the art, novel compounds isolated, produced and harvestedfrom monocotyldenous plants and methods for using the same to suppressappetite and promote weight loss in mammals would be a significantadvancement in the art. Such novel compositions and methods aredisclosed and taught herein.

BRIEF SUMMARY AND OBJECTS OF THE INVENTION

A primary object of the present invention is to provide novel chemicalcompositions derived, isolated, and/or extracted from monocotyldenousplants or by chemical synthesis, and methods of use to achieve weightloss in mammals.

It is another object of the present invention to provide novel chemicalcompositions derived, isolated, and/or extracted from monocotyldenousplants or by chemical synthesis, and methods of use to suppress appetitein mammals.

It is also an object of the present invention to provide novel chemicalcompositions derived, isolated, and/or extracted from monocotyldenousplants or by chemical synthesis, and methods of use to elevate mood inmammals.

It is a further object of the present invention to provide novelchemical compositions derived, isolated, and/or extracted frommonocotyldenous plants or by chemical synthesis, which function asmelatonin analogs and/or agonists in mammals.

In addition, it is an object of the invention to provide novel methodsfor growing monocotyldenous plants which results in an increased yieldof 6-MBOA and other phenolic and indole-amine compounds.

It is a further object of the present invention to provide novel methodsfor harvesting monocotyldenous plants which are efficient for producing6-MBOA and other phenolic and indoleamine compounds.

In addition, it is a further object of the present invention to providenovel chemical compositions derived, isolated, and/or extracted frommonocotyldenous plants or by chemical synthesis, and methods of use asadjunctive therapy in fibromyalgia.

It is also an object of the present invention to provide novel chemicalcompositions derived, isolated, and/or extracted from monocotyldenousplants or by chemical synthesis, and methods of use as adjunctivetherapy in sleep apnea.

Additionally, it is an object of the present invention to provide novelchemical compositions derived, isolated, and/or extracted frommonocotyldenous plants or by chemical synthesis, and methods of use asadjunctive therapy in diabetes.

It is a further object of the present invention to provide novelchemical compositions derived, isolated, and/or extracted frommonocotyldenous plants or by chemical synthesis, and methods of use asadjunctive therapy in hyperglycemia.

It is a still further object of the present invention to provide novelchemical compositions derived, isolated, and/or extracted frommonocotyldenous plants or by chemical synthesis, and methods of use asadjunctive therapy in arthritis.

It is also an object of the present invention to provide novel methodsfor growing and harvesting monocotyledonous plants to obtain phenoliccompounds with a phenolic molecule to which are covalently linked anoxygen-containing group, a nitrogen or second oxygen containing group,and at least one C₁-C₄ alkoxy group.

Additionally, it is an object of the present invention to provide novelmethods for promoting weight loss in mammals by administering phenoliccompounds with a phenolic molecule to which are covalently linked anoxygen-containing group, a nitrogen or second oxygen containing group,and at least one C₁-C₄ alkoxy group.

It is a further object of the present invention to provide novel methodsfor suppressing appetite in mammals by administering phenolic compoundswith a phenolic molecule to which are covalently linked anoxygen-containing group, a nitrogen or second oxygen containing group,and at least one C₁-C₄ alkoxy group.

It is also an object of the present invention to provide novel methodsfor growing and harvesting monocotyledonous plants to obtain precursorsof phenolic compounds comprising benzoxazinoids-cyclic hydroxamic acid,lactams and their corresponding glucosides.

Additionally, it is an object of the present invention to provide novelmethods for promoting weight loss in mammals by administering precursorsof phenolic compounds comprising benzoxazinoids-cyclic hydroxamic acid,lactams and their corresponding glucosides.

It is a further object of the present invention to provide novel methodsfor suppressing appetite in mammals by administering precursors ofphenolic compounds comprising benzoxazinoids-cyclic hydroxamic acid,lactams and their corresponding glucosides.

Consistent with the foregoing objects, and in accordance with theinvention as embodied and broadly described herein, it has been foundthat certain phenolic compounds and precursors of phenolic compounds,related to each other by shared structural similarities and havingstructural similarities with melatonin, are effective in bettering mood,improving sexual desire and performance, and as an adjunctive therapyfor weight loss and substance abuse and addiction. The novel compoundsof the present invention naturally exist as plant secondary metabolitesin the early growth of monocotyledonous plants, become concentrated fromtheir ingestion within certain animal parts, or can be synthesized bychemical means. The invention includes therapies using the novelcompounds of the present invention for treating depression and sexualdysfunction, as well as adjunctive therapies for achieving weight lossand problems of substance abuse and addiction. The therapeutic methodcomprises the ingestion of the novel compounds of the present inventionover a certain period of time, or other means for getting the compoundsof the invention into the body. Both males and females benefit fromingesting the compounds of the invention, while still contained in driedleaves from monocotyledonous plants with such compounds or taken aspurified and/or synthesized preparations. It appears that the compoundsof the invention act as antidepressants without the undesirable sideeffects of currently used antidepressants.

As discussed in greater detail hereinbelow, one presently preferredembodiment of the present invention comprises administration of phenoliccompounds belonging to related chemical families of which6-methoxy-2,3-benzoxazolinone (6-MBOA) is a member. These phenoliccompounds share a structural similarity with melatonin and indoleaminecompound. Based on structural similarities with melatonin, compounds ofthe invention were studied for their effects on weight loss, appetitesuppression and mood properties. In therapeutically effective amounts,novel compounds of the present invention may also be helpful asadjunctive therapies for conditions selected from the group consistingof arthritis, sleep apnea, fibromyalgia, diabetes and hyperglycemia.

In one presently preferred embodiment of a method of the presentinvention, particular emphasis is placed on promoting weight loss inmammals by the administration of a therapeutically effective amount of acomposition of 6-methoxy-2,3-benzoxazolinone or pharmaceuticallyacceptable salts thereof. In yet another presently preferred embodimentof the present invention, particular emphasis is placed on novel methodsof suppressing appetite in mammals by the administration of atherapeutically effective amount of a composition of6-methoxy-2,3-benzoxazolinone or pharmaceutically acceptable saltsthereof.

A source of the novel compounds of the present invention is inmonocotyledonous plants in their early growth stages. To obtain thesecompounds at concentrations suitable for human therapeutic use from suchmonocotyledonous plants, harvest of these plants at an early lifehistory stage and drying using explicit parameters, as well as specificanalytical criteria to ascertain suitability, are employed. However, itis also possible to get the compounds of the invention at concentrationssuitable for human therapeutic use from animals parts, including, butnot necessarily limited to, the velvet antler tips of deer and elk(Cervidae), where they become concentrated after ingestion by the animalof sprouting and otherwise immature grasses. The compounds of theinvention can also be obtained through chemical synthesis.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects and features of the present inventionwill become more fully apparent from the following description andappended claims, taken in conjunction with the accompanying drawings.Understanding that these drawings depict only typical embodiments of theinvention and are, therefore, not to be considered limiting of itsscope, the invention will be described with additional specificity anddetail through use of the accompanying drawings in which:

FIG. 1 shows the general chemical structures and parameters definingpreferred embodiments of compounds of the invention;

FIG. 2 shows the chemical structures for representative compounds ofpreferred embodiments of compounds of the invention;

FIG. 3 shows the effects of injecting representative compounds of theinvention on uterine weight in a rodent;

FIG. 4 summarizes the effects of consuming compounds of the invention byhuman males on depression or mood and sexual response;

FIG. 5 summarizes the effects of consuming compounds of the invention byhuman females on depression or mood;

FIG. 6 shows the 6-methoxy-2-benzoxazolinone contents of air-dried andfreeze-dried velvet antler samples from elk, Cervus elaphus;

FIG. 7 is a chart illustrating the effects of compounds of the inventionon weight and body mass index following oral administration over thirty(30) days in human males and females;

FIG. 8 is a chemical formula illustrating alternate embodiments ofcompounds of the invention; and

FIG. 9 is a series of chemical formulae showing chemical structures forrepresentative compounds of alternate embodiments of compounds of theinvention.

DETAILED DESCRIPTIONS OF THE PREFERRED EMBODIMENTS

It will be readily understood that the components of the presentinvention, as generally described and illustrated in the Figures herein,could be arranged and designed in a wide variety of differentconfigurations. Those of ordinary skill in the art will, of course,appreciate that various modifications to the details herein may be madewithout departing from the essential characteristics of the invention,as described. Thus, the following more detailed description of theembodiments of the compositions and methods of the present invention, asrepresented in FIGS. 1 through 9, is not intended to limit the scope ofthe invention, as claimed, but it is merely representative of thepresently preferred embodiments of the invention.

Referring to FIG. 1, the compounds of the invention have in common aphenol molecule to which are covalently linked an oxygen-containinggroup, a nitrogen- or another oxygen-containing group, and a C₁-C₄alkoxy group. Using standard conventions for depicting chemicalstructures, Formulas I-III in FIG. 1 disclose the chemical structuresand specific parameters defining the compounds of the invention. FormulaIV in FIG. 1 is a unifying formula depicting all compositions of theinvention.

It has been found that compounds of the invention, when ingested orotherwise introduced into the user's body, are effective for achievingweight loss, suppress appetite, improve mood and appear likewiseeffective in adjunctive treatment of fibromyalgia, sleep apnea,diabetes, hyperclycaemia and arthritis. The term adjunctive therapy isdefined as a therapy which is joined or added to the primary therapy,but is not meant to substitute for the primary therapy. The compoundsmay be administered in the form of ground parts of plants in which theynaturally occur, like the ground leaves of immature plants, or aspurified or chemically synthesized compounds in a pharmaceuticallyacceptable carrier.

The compounds of the invention may be administered orally in the form oftablets, capsules, suspensions, solutions or other means suitable forsuch ingestion, perhaps as an admixture with other compounds to enhanceabsorption into the blood stream or to otherwise assist in achieving thedesired effects. Likewise, oral administration is contemplated toinclude sublingual (i.e., under the tongue) dosage forms. The compoundsof the invention may also be delivered by intranasal (i.e., through thenasal structures) or transmucosal (i.e., across mucous membranes)administration.

The compounds of the invention may also be administered parenterally, asa subcutaneous, intramuscular or intravenous injection, or by way of animplant for sustained release. When administered parenterally, thecompounds of the invention are to be dissolved in physiologicallyacceptable liquid media and/or otherwise compounded in accordance withthe known pharmaceutical art. Another mode of administering thecompounds of the invention may be a transdermal patch, in which entry ofthe compounds of the invention into the body is facilitated viaacceptable and appropriate carrier molecules.

Unless otherwise defined, the technical, scientific and medicalterminology used herein has the same meaning as understood by thoseinformed of the art to which this invention belongs.

6-MBOA and related compounds may have actions in an area of the brain,which may be referred to as the pineal hypothalamic pituitary axis(PHPA), as melatonin agonists and at the α- and β-adrenergic cellreceptors in their own right. These properties may be considered toindicate desirable psychotropic effects in humans consequent to theadministration of 6-MBOA and related compounds. Whereas melatoninexacerbates symptoms of dysphoria in depressed people, 6-MBOA, as amelatonin agonist, works in contrary fashion and actually stimulates abetter mood.

There has previously been no suggestion to implicate the administrationof 6-MBOA and related compounds as conducive to weight loss and/orappetite suppression. Mood improvement with the compounds of theinvention appears to be accomplished through biochemical orphysiological pathways different than are those affected by the abovementioned prescription medications. Improved mood typically means thatserotonin levels have been somehow raised, and increased amounts ofserotonin may impart a feeling of satiety in a mammal. One result ofthis feeling may be a reduced food intake and there may additionally bea reduction in body weight.

The following examples will illustrate the practice of the presentinvention in further detail. It will be readily understood by thoseskilled in the art that the following methods, formulations, andcompositions of novel compounds of the present invention, as generallydescribed and illustrated in the Example herein, are to be viewed asexemplary of the principles of the present invention, and not asrestrictive to a particular structure or process for implementing thoseprinciples. Thus, the following more detailed description of thepresently preferred embodiments of the methods, formulations, andcompositions of the present invention, as represented in Examples 1-7,is not intended to limit the scope of the invention, as claimed, but ismerely representative of presently preferred embodiments of theinvention.

EXAMPLE 1 The Similar Physiological Effects of the Compounds of theInvention

Representative compounds of Formulas I, II, and III are shown in FIG. 2.The compounds of Formulas I, II and III have like physiologicalproperties, and as such may be considered as similar or equivalent fortherapeutic purposes, and were tested via a rodent model. Female montanevoles, Microtis montanus, received intra peritoneal injections ofrepresentative compounds belonging to Formulas I, II and III, and shownin FIG. 2, for three consecutive days and sacrificed twenty-four (24)hours after the last injection to examine uterine weight response. Toassess the properties of each representative compound, pure ones made bychemical means (University of Utah Department of Chemistry, Salt LakeCity, Utah) were prepared specifically for this test. All compounds wereinjected at a dose level of 5 mcg/day, dissolved in five percent (5%)propylene glycol for a total injection volume of 0.5 ml. Control animalsreceived 0.5 ml of five percent (5%) propylene glycol only. All voleswere 4-5 weeks old and weighed 25-29 g.

Referring now to FIG. 3, a chart illustrates that all compoundsbelonging to Formulas I, II and III caused a statistically significantincrease in uterine weights. On average, the uterine weight in volesreceiving these was 22.8 g, fifty percent (50%) greater than for thecontrol group. The greatest average weight increase, eighty-two percent(82%) more than the uterine weight for the control voles, was in thosefemales administered 6-methoxy-2-benzoxazolinone, but even the leasteffect of a compound belonging to Formulas I, II or III, that for5-methoxy-2-benzoxazolinone, entailed a thirty-two percent (32%)increase in uterine weight. The results show that physiological effectsor modes of action are held in common by the compounds of the invention.

EXAMPLE 2 Compounds of the Invention as an Antidepressant andAphrodisiac in Human Males

This component of the invention relates to a method for lesseningdepression and otherwise bettering mood or feelings of well-being, saidmethod comprising the administration to human males of an effectiveamount of one or more of the compounds of the invention, defined aboveand in FIG. 1. This component of the invention also relates to a methodfor treating sexual dysfunction or otherwise increasing sexual desireand performance, including but not necessarily limited to lackinginterest in sex, problems with arousal, not enjoying sex, and anxietyabout sexual performance, said method comprising the administration ofan effective amount of one or more of the active compounds of theinvention.

A double-blind crossover study was done on human males to test compoundsof the invention as a therapeutic agent for treating depression orotherwise elevating mood as well as bettering sexual function. The trialhad three phases, each two weeks in duration, during which participantstook compounds of the invention for one phase or two weeks. The dailydose was made up from compounds of the invention naturally contained inthe ground leaves from immature corn plants, 30-45 cm tall, standardizedwith synthesized 6-methoxy-2-benzoxazolinone, to a total of 15 mg6-methoxy-2-benzoxazolinone. A dose of fifteen milligrams (15 mg) wasselected because this was considered a likely minimum effective dailyamount for humans, extrapolated from prior studies on rodents, rabbitsand other animals. Previous anecdotal trials on humans done by theinventors suggested that a 15 mg daily dose had a desirable effect, butno adverse consequences to health. In general, therapeutically effectiveamounts of compounds of the invention may be found in a daily dosagerange of between about 5 micrograms (mcg) to about 60 mg.

Weekly assessments of depression or mental well being and sexualfunction were done via widely accepted indices: to quantify depressionand generalized anxiety disorders, the Hospital Anxiety and Depressionscale (HAD); and for sexual desire, psychological arousal, and overallsexual outlook, the Arizona Sexual Experience Index (ASEX).

Phase One lasted 14 days, during which participants took daily doses ofthe invention or a placebo. Assignation of the invention or placebo tomale participants was done randomly. Immediately prior to the 14 dayscomprising Phase One, an initial physical examination and blood analysiswere done. At that time, each male filled out HAD and ASEX forms toassess mental well being and sexual function, was checked for sittingand standing blood pressure and pulse, and gave the blood sample neededfor the biochemical analyses.

Phase Two consisted of a seven-day period immediately after Phase One,during which neither invention nor placebo was taken. During Phase Two,physical examination and laboratory analyses were again done. In PhaseThree which lasted 14 days, participants again took either invention ora placebo. Assignation of the invention or placebo was done according tothe sort of capsule taken during Phase One. If a participant took acompound of the invention in Phase One, then placebo was administeredduring Phase Three, and vice versa. Immediately after finishing PhaseThree, a physical examination and laboratory analyses were again done.After completing Phase Three, each participant was asked preparedquestions as well as solicited for any comments and impressionsconcerning invention use.

As illustrated in FIG. 4, the results are tabulated and these dataindicate that the compounds of the invention have significant positiveeffect on depression or mood. Fourteen (14) of the fifteen (15)participants properly completed the study and only data for theseindividuals were used for analysis. HAD scores exceeding 20.0 denoteclinical depression, but lower ones can also be associated withdispirited mood. Only two males entered the trial with HAD valuesexceeding the clinical minimum (21.0 and 23.0). Still, twelve (12) offourteen (14) subjects showed bettered mood, improved feelings of wellbeing or lessened depression after taking compounds of the invention.Decreases in HAD scores over the two-week timespan were as much as 15and averaged 5.2. The two clinically depressed subjects showed decreasesin HAD values of 5.0 and 15.0. The average HAD score went from 13.5 atthe onset of the study to 9.1 after two weeks of taking compounds of theinvention, very significant statistically. Participants showed nostatistically detectable changes while taking placebo.

After taking compounds of the invention for two weeks, five (5) offourteen (14) participants had lessened ASEX values, indicating improvedsexual response or lessened sexual anxiety, while only two (2) offourteen (14) males showed the same after two weeks on placebo.Statistical significance was not found for the ASEX changes, but suchcould be attributed to a small sample size. Sexual benefits of thecompounds of the invention were also obviated in the trial through theexit interviews given to all participants. While taking these, amajority of males reported morning erections of the penis greater insize, duration or frequency than usually experienced when not taking thecompound. Also, comments by the majority centered about feeling “like ateenager” (direct quote) in terms of energy, sexual and otherwise. Itshould be noted that personal situations were complicated by unwillingor lacking sex partners. Twelve (12) of fifteen (15) participants alsoexpressed an unsolicited desire to continue using the compounds of theinvention. They stated a belief that the compounds of the inventioncould prove useful to them in a sexual context.

EXAMPLE 3 Compounds of the Invention as an Antidepressant in HumanFemales

This example further relates to a method for lessening depression andotherwise bettering mood or feelings of well-being, said methodcomprising the administration to human females of an effective amount ofthe compounds of the invention, defined above and in FIG. 1. Compoundsof the invention were used to treat eight females with clinicaldepression, which for three females had been ongoing for at least oneyear. Participants took the same dose of compounds of the invention asin Example 2, 15-mg each day. A HAD was administered to participantsprior to beginning daily doses. Each participant was interviewed everytwo weeks to check for adverse side effects and for comments on use ofthe compounds of the invention. A HAD Index was again administered uponcompletion of the six-week trial.

Referring to FIG. 5, results of the study are tabulated. These dataindicate that the compounds of the invention significantly lessendepression. Initial HAD scores exceeded 20 for all subjects. All femaleswere clinically depressed, and their HAD scores averaged 21.9. Six (6)of eight (8) participants showed responses to compounds of the inventionin which HAD values decreased 5-16 points, an average decrease of 10.5over the six-week timespan. The overall average HAD score decreased from21.9 (clinically depressed) at trial onset to 14.4 (not clinicallydepressed) after six weeks of use, with two participants ending with HADvalues of eight (8) and seven (7). There were only eight females in thetrial, but decreases in HAD scores were still statistically significant(p<0.031). The antidepressant properties of the compounds of theinvention are obviated.

Both excess weight and substance abuse are characterized by eitherprimary or secondary depression. Since such psychological factorsaffecting excess weight and substance abuse must be treated along withthe physiological ones for therapies to be effective in the long term,the compounds of the invention comprise adjunctive treatments forachieving weight loss or reducing the risk of relapse in persons withsubstance abuse or addiction problems.

EXAMPLE 4 Compounds of the Invention at Concentrations Suitable forHuman Therapies from Plants Harvested and Processed in Unique Fashion

Example 4 relates to a method for obtaining compounds of the inventionat concentrations suitable for human therapies from plants grown to animmature stage of growth. “Concentrations suitable for human therapies”means that compounds of the invention in 10 grams or less of dried plantmaterial make up a daily dose (e.g., 15 mg compounds of the invention as6-methoxy-2-benzoxazolinone; however, general therapeutically effectivedaily dosages of compounds of the invention may be between about 5 mcgto about 60 mg). Said dosage may include either the novel compound as itnaturally occurs or synthetically, or a combination of both natural andsynthetic novel compounds of the present invention.

Specific harvesting and drying conditions are specified herein, as areanalytical parameters for determining crop quality. By “specificharvesting and drying conditions”, it is meant that compounds of theinvention are obtained from plants via circumstances differing from theusual manner in which the plants are handled for the terminal product.

As an example, corn, Zea mays, is typically grown to its adult ormatured states for its seed-laden cob. At the immature growth stage atwhich compounds of the invention occur, corn plants have a biomass thatportends harvest of a substantial amount of leaf material containing thecompounds of the invention at concentrations suitable for humantherapies. Hence, dried corn leaves from immature plants becomeappropriate for the human therapies elucidated herein, or the driedleaves are a resource for the concentration, extraction and purificationof the compounds of the invention. There are other monocotyledonousplants with the natural production of compounds of the invention atconcentrations suitable for human therapies.

Monocotyledonous flowering plants belong to the plant order of Lilidae(sometimes referred to as a subclass or superorder), which may comprisethe following plant families: Alismataceae (water-plantains), Araceae(lords-and-ladies), Butomaceae, Cyperaceae (cotton-grasses, spike-rushesand sedges; sometimes referred to as a plant order), Dioscoreaceae(black bryony), Hydrocharitaceae (waterweeds), Iridaceae (irises),Juncaceae (rushes and wood-rushes), Juncaginaceae, Lemnaceae(duckweeds), Liliaceae (lilies, onions and bluebells), Orchidaceae(orchids), Poaceae (grasses—also named Graminae), Potamogetonaceae(pondweeds), Sparganiaceae (bur-reeds), Typhaceae (bulrushes), andZosteraceae. It is contemplated that compounds of the invention may bederived, isolated, harvested and/or extracted from monocotyledonousplants selected from any of the above identified plant families and/ororders. Preferred embodiments of compounds of the invention may beselected from the families of Cyperaceae and Poaceae (also referred toas Graminae). These families include the cereal grasses (e.g., corn,wheat, barley, oats, rice and rye) and the hay and pasture plants (e.g.,sorghum, sugarcane, timothy, bent grass, bluegrass, orchard grass, andfescue). These families may also include wild grasses, millet, bamboo,Job's Tears (Coix lachryma-jobi; Coix aquatica) and other barley-likegrasses.

Monocotyledonous plants as sources of compounds from preferredembodiments of the invention may be selected from the group consistingof corn, wheat, barley, rye, oats, rice, sorghum, millet, bamboo, Job'sTears, barley-like grasses, and wild grasses, by growing the plant to animmature life history stage (i.e., before plant maturity) and harvestingthe plant. The example of corn, Zea mays, is not intended to be limitingto the scope of the source of compounds of the invention. In all cases,harvest and processing needs to be done in a novel and unique fashionrelative to the usual manner in which the plants are handled, and theanalytical parameters for indirectly determining crop quality withrespect to the compounds of the invention, described below, areapplicable.

Growing corn to obtain the compounds of the invention is initially donein a conventional fashion, but seeds are planted more densely than isthe case for conventional crops because of the smaller size of plants atharvest. Harvest time is done while plants are immature. For corn, thisimmature plant harvesting may happen when plants are no more than aboutthirty (30) to about forty-five (45) centimeters tall, about five weeksafter planting. Preferably, embodiments of the invention may alsoutilize harvesting immature corn plants that are between aboutforty-five (45) centimeters to about 122 centimeters in height, andbetween about five weeks to about eight weeks after planting are soughtand preferably less than ten weeks. As a general reference, mature cornplants are typically more than 180 centimeters in height and are grownfor about four (4) to about five (5) months after planting. For corn,harvesting is preferably done by cutting plants at 3-4 centimeters abovethe ground. Severed plants may be gathered and may be dried attemperatures held at about 40° Celsius (C.) to about 45° C. Empiricalstudies showed that this temperature range helps maximize conversion ofthe precursors of compounds of the invention to the active molecules.

In a trial plot in southern Illinois, approximately 38,000 corn plantsyielded 137 kilograms (300 pounds) of dried (96% dry weight) corn leaveswith suitable levels of compounds of the invention. Analyses via massspectroscopy showed that substantive amounts of the compounds of theinvention were in dried corn leaves after five (5) weeks of growingtime. Five (5) random samples of dried corn leaves were obtained foranalysis. For each dried corn leaf sample, a one-gram portion washomogenized in 10-ml distilled water, incubated at 25° C. for one (1)hour, boiled for thirty (30) min, and then centrifuged for ten (10) minat 3600 rpm. The resulting supernatant was extracted three (3) timeswith ten (10) ml reagent-grade dichloromethane per extraction. The three(3) extracts were combined and allowed to air dry, after which the driedresidue was stored in a tightly stoppered glass tube.

The dried residue was analyzed for 6-MBOA by gas-chromatographic massspectroscopy. A Dupont Model DP102 device with an integrator and aSP2250 GC column isothermal at 200° C. (Dupont, Wilmington, Del.) wasused. A standard curve for 6-MBOA was obtained using 0.06-, 0.60- and1.20-.mu.g injections of pure, synthetic 6-MBOA (Sigma, Saint Louis,Mo.) in methanol solution and was reproducible at a five percent (5%)level.

6-MBOA occurred in dried corn leaves at levels suitable for humanconsumption. Samples averaged ten (10) mg/g 6-MBOA, with individualsamples assaying as follows: eight (8), nine (9), ten (10), ten (10),and twelve (12) mg/g 6-MBOA, respectively. At such concentrations, lessthan two (2) grams dried corn leaves are needed to make up a daily humandose. This makes corn leaves, as uniquely grown, harvested and driedherein, a suitable source of compounds of the invention. For comparisonpurposes, leaves from plants grown more than eight (8) weeks wereanalyzed for 6-MBOA. Virtually none was present.

Previous work by the inventors indicated that higher levels of thecompounds of the invention are associated with multiple biochemicalparameters that indicate crop quality or adequacy with respect to thecompounds of the invention. In those plants containing compounds of theinvention at concentrations suitable for human use total phenols are atconcentrations greater than 17.0 mg/gm (dry weight) but combined amountsof 4-hydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic acid total nomore than 1.5 mg/gm (dry weight), as determined through chromatography.For invention, the above mentioned parameters for total phenols andcombined amounts of 4-hydroxycinnamic acid and4-hydroxy-3-methoxycinnamic acid are instituted here as elements of theinvention as it pertains to plants. For the corn leaf samples of FIG. 4,total phenols averaged 19.1 mg/gm and the cumulative total for cinnamicacids averaged 0.9 mg/gm.

EXAMPLE 5 Compounds of the Invention from Parts of Animals

The main food of deer and elk (Cervidae) for most of the year is browse,the growing tips of low-growing, woody plants. However, casting of hardantlers from the previous year coincides with a spring flush in naturalpasturage and an accompanying shift to a diet of grasses, chieflysprouting and immature ones. Such grasses are at developmental stages inwhich 6-MBOA and related compounds are most prevalent.

After casting, new antlers begin their development. These growingantlers are nourished by blood vessels from a covering of skin, calledvelvet. An antler grows from the tip with tissue laid down as the tipadvances. A velvet antler tip has a soft cartilaginous internalstructure and high fat content, contrasting the rest of the antler withits ossified cartilage and little fat.

Air-dried and freeze-dried velvet antler samples were obtained. Thesecame from commercially farmed Canadian Wapiti and New Zealand red deer,both subspecies of elk, Cervus elaphus. All animals had been maintainedon grassy pasturage. The samples were from velvet antlers that had beengrowing fifty-five (55) to sixty-five (65) days, and included both tips,defined as the region five (5) cm or less in length starting at theapex, as well as other, more matured parts of the antler.

For each sample of dried antler, a one-gram portion was homogenized inten (10)-ml distilled water, incubated at 25° C. for one (1) hour,boiled for thirty (30) min, and then centrifuged for ten (10) min at3600 rpm. The resulting supernatant was extracted three (3) times withten (10) ml reagent-grade dichloromethane per extraction. The three (3)extracts were combined and allowed to air dry, after which the driedresidue was stored in a tightly stoppered glass tube.

The dried residue was analyzed for 6-MBOA by gas-chromatographic massspectroscopy. A Dupont Model DP 102 device with an integrator and aSP2250 GC column isothermal at 200° C. (Dupont, Wilmington, Del.) wasused. A standard curve for 6-MBOA was obtained using 0.06-, 0.60- and1.20-.mu.g injections of pure, synthetic 6-MBOA (Sigma, Saint Louis,Mo.) in methanol solution and was reproducible at a five percent (5%)level.

Referring to now FIG. 6, results are shown and these data indicate6-MBOA was present in all tip samples, with little or none present inthose from the more matured parts of the antler. Notably, amounts of6-MBOA from velvet antler tips exceeded those typically found in grassesless than a week after sprouting, the stage of growth with the most6-MBOA. These results show that ingested 6-MBOA is accumulated orconcentrated in velvet antler tips, and as such represent a means forobtaining the compounds of the invention in concentrations suitable forhuman use.

Many animals eat grasses and other monocotyledonous plants. Such animalsmay also be accumulating compounds of the invention in body parts, mostlikely in those characterized by high fat contents. Obtaining compoundsof the invention from body parts other than the antlers of elk and deerand from animals other than elk or deer are not precluded frominvention.

EXAMPLE 6 Compounds of the Invention for Weight Loss

Recruitment of Participants

Overweight human females and males were preferentially recruited forthis look at weight loss properties of the compounds of the invention.For reasons of safety, precluded from participation were individualswith moderate or worse hypertension (Systolic>160, Diastolic>100); Class2 or Morbid Obesity (Body Mass Index>35, see below); and/or healthproblems of a debilitating, life-threatening or otherwise serious nature(multiple sclerosis, emphysema, diabetes, etc.). Twenty-four (24)individuals had been initially screened, while fourteen (14) females andsix (6) males ultimately took part in the study. Ages of the twenty (20)participants ranged from thirty-one (31) to fifty-four (54) years, andaveraged thirty-eight (38) years.

Test and Control Groups

The twenty (20) participants were randomly assigned to Test and ControlGroups, with ten (10) participants in each group. In particular, thoseparticipants in the “Test Group” were given the novel compounds of thepresent invention which were produced and delivered in gelatin capsules(e.g., Size 00). The novel compounds of the invention were obtained fromappropriately chosen, grown, dried and ground leaves from the corn plant(Zea mays), further to the methods of harvesting as describedhereinabove. In one presently preferred embodiment, the dosage wasstandardized to 6-MBOA content, for which daily cumulative dose wasninety (90) micrograms for each participant. Although it will beappreciated that compounds having the general chemical structure as setforth in formulae I, II, III, and generally as IV, as shown in FIGS. 1and 2, 6-MBOA was used in the present exemplary study. It will beappreciated, therefore, that other novel compounds of the presentinvention, consistent with the general chemical structure as set forthin formulae I, II, III, and IV are within the spirit and scope of thepresent invention.

Moreover, the novel compounds of the present invention may be derived,isolated, and/or extracted from monocotyledonous flowering plants belongto the plant order of Lilidae, consistent with the harvesting methodsdescribed hereinabove or by means of chemical synthesis. It is furthercontemplated that the novel compounds of the invention may be obtainedby a combination of harvesting from natural sources, as describedhereinabove, and by chemical synthesis. Delivery of a dosage of thenovel compounds of the present invention may include either the novelcompound as it naturally occurs or synthetically, or a combination ofboth natural and synthetic.

Those participants in the “Control Group” were given ground, driedparsley leaves (Petroselinum hortense) delivered in gelatin capsules(e.g., Size 00). This placebo preparation comprising parsley visuallyresembled capsules containing the compounds of the invention, but wasinstead made from a plant well recognized as having no effects on weightloss or other aspects of weight control; on mood, depression or feelingsof well being; and/or on sexual function, arousal, or performance.

Study Design

Participants were subjected to the same administration schedules withoutknowledge as to whether they belonged to the Test Group or the ControlGroup. All were instructed to take two (2) capsules at 0.5-1.0 hourbefore meals, three (3) times per day, for thirty (30) successive days.Participants were told that they were receiving a dietary supplementthat might better mood and otherwise improve disposition or outlook, butwere not instructed that the formulation might affect weight or effectweight loss. Furthermore, “overweight” had been a long-term conditionfor virtually all participants. Because of these pre-existing eatingbehaviors and the fact that participants were blinded to the knowledgethat involvement in the study might lead to weight loss, independentassignment of participants to either the Test Group or Control Group wasnot believed to significantly effect eating behaviors and associatedweight consequences.

Visits and Measurements

At the beginning of the study, participants in both the Test Group andthe Control Group were given the self administered Goldberg DepressionScale to maintain the illusion of a mood-related study. All participantsalso had their blood pressures taken and were weighed (done beforebreakfast while nude or in underwear; measured on a calibratedelectronic scale to the nearest 0.1 kilograms) prior being given thenovel compounds of the present invention or placebo, respectively. Allparticipants were also weighed at the end of the study (e.g., thirty(30) days). The height of each participant, while barefoot or wearingsocks, was determined only at the onset of the study, whereas Body MassIndex (BMI) values were calculated both at the onset and at the end ofthe study. As known in the art, BMI is a measure of body fat, and thusweight-related health risks, based on height and weight that applies toboth adult men and women. BMI is generally calculated as follows:

BMI equals a person's weight in kilograms divided by height in meterssquared; or

${BMI} = {\frac{{Weight}\mspace{14mu}{in}\mspace{14mu}{Kilograms}}{\left( {{Height}{\mspace{11mu}\;}{in}\mspace{14mu}{Meters}} \right) \times \left( {{Height}\mspace{14mu}{in}\mspace{14mu}{Meters}} \right)} = {{kg}\text{/}{m2}}}$

A BMI over thirty (30) is typically considered obese; a BMI betweentwenty-five (25) and 29.9 is typically considered overweight; and a BMIbetween 18.5 and 24.9 is typically considered healthy. Older people tendto have more body fat than younger adults with the same BMI, and someclinicians consider BMI values under twenty-seven (27) to be normal andhealthy for individuals over forty (40) years old.

Statistical Analysis

With only ten (10) participants in each Group, assuming normaldistributions for the data was inappropriate. In order to compensate fora potentially non-normal distribution of study data, a non-parametrictest was utilized for statistical analysis. As known in the art, theWilcoxon-Mann-Whitney U Test (sometimes referred to as the Wilcoxon RankSum Test) is one of the more powerful of non-parametric tests forcomparing data distributions in two populations (e.g., Test Group andControl Group).

Results

Referring specifically now to FIG. 7, the weight and BMI for each of thestudy participants is illustrated showing the pre-treatment andpost-treatment results following thirty (30) days of oral administrationof the 6-MBOA compound of the present invention, or alternatively, aplacebo. Primary interests centered about changes in absolute bodyweight after taking the 6-MBOA compound of the invention for thirty (30)days. Both the participants in Test Group and the Control Group showedweight loss and BMI decreases, but magnitudes of the weight lossdiffered. For “Weight”, the Test Group showed a nine-fold greater lossthan did the Control Group, or almost about one (1) kilogram on averagein the Test Group contrasting to about 0.1 kilograms in the ControlGroup. BMI values also decreased three-fold more for the Test Group, incomparison to the Control Group.

On a case-by-case basis, differences between participants in the Testand Control Groups were even more striking. Seven (7) of the ten (10)participants in the Test Group experienced losses ranging from about 1.1to about 2.9 kilograms, and averaging about 1.8 kilograms. In theControl Group, some of the participants (five (5) of the ten (10)) lostweight. However, the amount of weight lost in the Control Group wassubstantively less than in the weight loss of the participants in theTest Group. The weight lost in the Control Group ranging from about 0.4to about 1.3 kilograms and averaging only about 0.8 kilograms.

With the Wilcoxon-Mann-Whitney U Test, the null hypothesis was thatmedians did not differ between the participants in the Test and ControlGroups. In “Difference” for “Weight”, the Test Group median differedsignificantly from the Control one (U=27.0; P=0.04). On average, moreweight was lost by Test Group participants than by Control Groupparticipants. Differences between the Test and Control Groups for“Weight” at the “Beginning” were not significant (U=32.5; P=0.10),meaning that baseline weights in the Test and Control Groups may havebeen similar. On the other hand, “Weight” at the “End” did significantlydiffer (U=28.5; P=0.05). The results therefore support a finding thatweight reduction is better associated with having taking the novelcompounds of the present invention for a period of about one month.

BMI comparisons did not reveal statistical differences, but this waslargely due to the small sample size. The statistical problem withsmaller sample size may be appreciated for example, and not by way oflimitation, by looking at differences in “End” values for the Test Groupversus the Control Group. These “End” values between the groups were notgreat enough to show as significantly different (U=34.0; P=0.12).Results for “Difference” between the Test Group and Control Group(U=31.5; P=0.08) were also not significant. However, the mean value for“Difference” decreased three-fold more in the Test Group (−0.3) than inthe Control Group (−0.1). This disparity in the mean values for“Difference” is further evidence that the novel compounds (e.g., 6-MBOA)of the present invention may contain weight loss properties. With agreater number of participants (i.e., greater study size sample),significant results between the Test and Control Groups comparisons andeven more profound demonstration of weight reduction from using thenovel compounds of the present invention are considered to be highlylikely.

Discussion and Conclusions

As disclosed herein, novel compounds of the present invention positivelyaffect mood. It was therefore hypothesized by the inventors that thenovel compounds of the present invention may have weight lossproperties. This example or study is consistent with the initialhypothesis and premise.

Weight loss by the Control Group participants (significantly less thanthe Test Group), may be attributed to the placebo effect. The placeboeffect is a psychological phenomenon, due to belief in a treatment or toa subjective feeling of improvement. According to the placebo effect itwas believed plausible that participants in the Control Group might havesome weight loss due to their expectation that they might be receivingan agent which could improve mood. It is possible that the expectationof an improved mood, regardless of reason, could result in a reducedcaloric intake, and subsequently result in weight loss. Even with thepossible placebo effect, the significant nine-fold greater weight lossin the Test Group versus the Control Group is supportive that the novelcompounds of the present invention are an effective weight losstreatment or regimen.

Given the weight loss demonstrated herein, both beta-adrenergicagonistic and alpha-adrenergic antagonistic receptor effects areconsidered consequences of using the novel compounds of the presentinvention. As earlier stated, the novel compounds of the presentinvention have been shown to be beta-adrenergic agonists. In regard tofat cells, beta-adrenergic agonist activity is considered fundamentalfor releasing lipids and thus achieving lipolysis or fat loss. Not onlydid the compounds of the present invention effect mobilization of fattyacids or lipids from fat cells, but these compounds did this withoutharsh side effects, such as the jitters and hypertension associated withephedrine-based products. The weight loss realized by participants inthe Test Group also indicates alpha-adrenergic (e.g., alpha2-adrenergic) antagonist activity with the novel compounds of thepresent invention, given that such activity facilitates mobilizationfrom fat cells of lipids that otherwise might not be released veryeasily. Alpha-adrenergic antagonists like the novel compounds comprisingthe present invention are particularly desirable for purposes ofreducing those areas of fat storage considered more difficult to trim,like the obliques in men and lower body in women.

In consort with their weight loss properties, the novel compounds of thepresent invention also act as appetite suppressants, sometimes referredto as appetite depressants. As known in the art, appetite suppressantsare generally referred to as agents for decreasing appetite such thatcaloric intake and perhaps ingestion of certain foods are reduced. Theseproperties of the novel compounds of the present invention may bedemonstrated by the effect on food consumed, both by type of food andcaloric intake, by those participants who were administered the novelcompounds of the present invention.

Interviews with the participants revealed that, prior to the onset ofthe study, caloric intake by certain overweight female participants,(four (4) of the seven (7) Test Group women—the lesser overweightparticipants (BMI average 26.6)), was 2,100 kilocalories (kcal) per dayon average. The average value for women of normal body weight is 1,900kcal per day. This is a difference of only ten percent (10%) and mayhave included such factors as poor diet selections and physicalinactivity in the overweight female participants.

Women of normal body weight tend to eat whole grains, fruits,vegetables, low-fat protein sources and foods otherwise considered to beof a healthful and nutritious nature. Items high in carbohydrates andfats, along with low quantities of fiber and protein figured prominentlyin the diets of the overweight women in the study. For example, onefemale participant had a propensity to eat an abundance of bread orpastries in lieu of or along with other foods, while another femaleparticipant routinely skipped breakfast but also snacked on chocolatecandy bars and sugar-fortified carbonated beverages.

The three (3) remaining participants had been routinely eating even moreat the onset of the study, with their initial caloric consumptionranging from about 2,400 kcal to about 3,000 kcal per day, with about2,700 kcal on average. These participants had a mean BMI of 30.1 andwere generally more overweight than the other four (4) Test Groupfemales (BMI average 26.6). Although the three (3) remaining femaleparticipants consumed about 600 kcal per day more than did the otherfemales participants in the Test Group, all female participants wereuniform in that foods of lesser nutritional quality made up prominentportions of their diets.

After administering the compounds of the invention for thirty (30) days,the average caloric intake for the four (4) females with lesser BMI(average 26.6) had decreased by more than 100 kcal per day. Theseparticipants also reported lessened cravings for certain food items. Forexample, the female participant who skipped breakfast and consumedchocolate candy bars and sugar-fortified carbonated beveragesexperienced decreased desire for these food items and decreased her bodyweight by 2.9 kilograms. In addition, the female participant who ate ahigher proportion of bread and pastries decreased her intake of suchitems and decreased her body weight by 1.4 kilograms.

Similar results and observations were seen in the overweight femaleswith an average BMI of 30.1 when the study began. They also experiencedreduced caloric intakes while receiving compounds of the invention, anddecreased body weight, on average, by about 1.8 kilograms. Moreover,these three (3) female participants reported their desire to eat hadabated by the end of the thirty (30) day test period. The data andobservations of the study illustrate significant activity of thecompounds of the present invention in reducing a desire to consumesugars, simple carbohydrates (e.g., snack foods) and unhealthy saturatedfats (e.g., snack foods and meats). In this group of overweight femaleparticipants, average daily food intake was reduced by about 230 kcalfollowing the thirty (30) days administration of the compounds of thepresent invention. It has been found, therefore, that compounds of thepresent invention are responsible for suppression or depression ofappetite in the participants in the Test Group.

Given that the novel compounds of the present invention have both weightloss and mood bettering properties, such properties may prove to be abeneficial therapy for arthritis. It is well known in the art, thatosteoarthritis is a degenerative joint disease and the most common formof arthritis. Unlike joint problems caused by swelling or inflammation,osteoarthritis stems primarily from a breakdown of the connectivetissues that bind muscles and bones together. The ensuing damageincludes deterioration of joint surfaces, which no longer mesh smoothlyand instead cause considerable pain. Joint problems are usually worsenedby excessive weight. For example, the knees bear a considerable loadeven during such simple activities as walking, whereas any decrease inoverall body weight can positively affect the performance or quality oflife in arthritic individuals. Meanwhile, preparations that improve moodhave been found to ameliorate the debilitating pain associated witharthritis or otherwise better tolerance of arthritic conditions.

Likewise, the novel compounds of the present invention may beadvantageous to diabetic and hyperglycemic people, for whom weight lossand mood enhancing medications can improve glycemic control. Thecompounds of the present invention also provide applicable therapy forother disorders. For example, weight loss may improve physicalfunctioning in fibromyalgia patients, while mood-enhancing medicationsmay alleviate other adverse symptoms of this condition. Weight loss mayalso help eliminate or otherwise diminish sleep apnea, making the novelcompounds of the present invention valuable for treatment of thiscondition.

EXAMPLE 7 Alternative Embodiments of the Novel Compounds

Generally referring to FIGS. 8 and 9, any number of alternativeembodiments of precursors of phenolic compounds of the present inventionmay be contemplated as falling within the spirt and scope of the presentinvention. In particular, Formula V is a general chemical formuladepicting a generic representation of alternative embodiments ofprecursors of phenolic compounds of the present invention as illustratedin FIG. 8. As shown, such embodiments of novel compounds of the presentinvention may include benzoxazinoids-cyclic hydroxyamic acids, lactams,and corresponding glucosides. As contemplated herein, substitution atthe “R¹” position may be accomplished with a member selected from thegroup consisting of H and OCH₃. Substitution at the “R²” position may beaccomplished with a member selected from the group consisting of H andglucose (as a glucoside). Substitution at the “R³” position may beaccomplished with a member selected from the group consisting of H, OH,and OCH₃.

Referring now to FIG. 9, a series of chemical formulae, according to thegeneric representation shown in FIG. 8, illustrate chemical structuresfor representative compounds of further embodiments of novel compoundsof the present invention. Specifically, FIG. 9 a illustrates a chemicalformula for 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA). DIBOA may alsohave a glucose molecule to form a glucoside (also referred to as aglycoside), DIBOA-Glc, which is shown in FIG. 9 b. As illustrated, FIG.9 c depicts a chemical formula for2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA). DIMBOA may alsoexist in combination with glucose molecule to form a glycoside compound(DIMBOA-Glc), which is shown in FIG. 9 d. FIG. 9 e illustrates achemical formula for 2-hydroxy-1,4-benzoxazin-3-one (HBOA). A glycosidemay also form between HBOA and a glucose molecule (HBOA-Glc) and isshown in FIG. 9 f. FIG. 9 g depicts a chemical formula for2-hydroxy-7-methoxy-1,4-benzoxazin-3-one (HMBOA). HMBOA may also containa glucose molecule to form HMBOA-Glc, which is depicted in FIG. 9 h.Additionally, FIG. 9 i, illustrates a chemical formula for2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one (HDMBOA). Wherein, FIG. 9 jillustrates an glucoside formed between HDMBOA and glucose (HDMBOA-Glc).

In the foregoing examples, glucose molecules may be bonded to arespective aglycone (i.e., non-sugar) compound (e.g., DIBOA, DIMBOA,HBOA, HDMBOA, 6-MBOA) to form a glycoside. As appreciated, glucosemolecules typically are in the form of a pyranose (i.e., cyclic 6-carbonring), which may be referred to as a glucopyranose. Glucopyranosecompounds usually bond with the aglycone portion as an hemiacetal.Configurations of glycoside compounds in yet other presently preferredembodiments of the present invention may be found in the(2R)-configuration. It is intended, however, that other forms of glucoseand configurations of glycosides are contemplated to be within the spirtand scope of the novel compounds of the present invention. It isintended, therefore, that the presently preferred embodiments of novelcompounds of the present invention, as shown in Example 7, be viewed asexemplary of the principles of the present invention, and not asrestrictive to any particular formula, structure, or method forimplementing and/or practicing the present invention.

Since the novel compositions of phenolic compounds and precursors ofphenolic compounds of the present invention are configured to promoteweight loss, suppress appetite, and enhance mood, it will be readilyappreciated that a method for promoting weight loss, suppressingappetite and for enhancing mood includes phenolic compounds belonging torelated chemical families of which 6-methoxy-2,3-benzoxazolinone(6-MBOA) is a member as described hereinabove and in the figures. It isintended, therefore, that the examples provided herein be viewed asexemplary of the principles of the present invention, and not asrestrictive to a particular structure or method for implementing thoseprinciples.

It will be further appreciated that the novel compositions of phenoliccompounds and precursors of phenolic compounds belonging to relatedchemical families as defined herein and in the figures of which6-methoxy-2,3-benzoxazolinone (6-MBOA) is a member, may be administeredin any manner known to those ordinary skill in the art, including butnot limited to, oral, parenteral, sublingual, topical, transdermal,intramuscular, or inhalation, and may also contain excipients chosen inaccordance with the dosage form adopted. Moreover, the dosage of theextract compositions given to an individual may vary on the basis ofseveral considerations without departing from the spirit and scope ofthe present invention and will, accordingly, depend on the targetedindividual's particular case to be treated.

From the above discussion, it will be appreciated that the presentinvention provides methods of promoting weight loss, suppressingappetite or enhancing mood using phenolic compounds and precursors ofphenolic compounds belonging to related chemical families of which6-methoxy-2,3-benzoxazolinone (6-MBOA) is a member. While specific doselevels are used in the Examples, these are merely examples and effectivedose levels may vary to a large extent, and preferred dose levels mayvary with the conditions being treated and the size or sex of the personbeing treated. Dose levels do not appear to be critical as long as aneffective amount is given.

Whereas this invention is here illustrated and described with referenceto embodiments thereof presently contemplated as the best mode ofcarrying out such invention in actual practice, it is to be understoodthat various changes may be made in adapting the invention to differentembodiments without departing from the broader inventive conceptsdisclosed herein and comprehended by the claims that follow. All changeswhich come within the meaning and range of equivalency of the claims areto be embraced within their scope.

1. A process for promoting weight loss and/or suppressing appetite in amammal by the administration of an amount of a composition defined as:

wherein “R¹” is selected from the group consisting of H and OCH₃;wherein “R²” is selected from the group consisting of H and Glucose (asa glucoside) wherein “R³” is selected from the group consisting of H,OH, and OCH₃; or or a phannaceutically acceptable salt thereof, saidamount of said composition being sufficient to promote weight lossand/or suppress appetite in said mammal, wherein said composition isobtained from at least one of (i) a leafy and/or immature plant part ofone or more monocotyledonous plants, (ii) animal tissue or (iii)chemical synthesis.
 2. A process as defined in claim 1, wherein saidamount of said composition comprises a daily dosage of between about 5mcg and about 60 mg.
 3. A process as defined in claim 1, wherein saidamount of said composition comprises a daily dosage of 15 mg.
 4. Aprocess as defined in claim 1, wherein said composition is isolatedand/or extracted and/or purified from the leafy and/or immature plantpart of one or more monocotyledonous plants selected from the groupconsisting of corn, wheat, barley, rye, oats, rice, sorghum, millet,bamboo, Job's Tears, barley-like grasses, and wild grasses.
 5. A processas defined in claim 4, wherein said leafy and/or immature plant part isdried before isolating and/or extracting and/or purifying saidcomposition therefrom.
 6. A process as defined in claim 5, wherein saidplant part is dried at a temperature in the range of between about 40°C. and about 45° C.
 7. A process as defined in claim 5, wherein saiddried plant part contains phenols in total amounts greater than 17.0mg/gm (dry weight).
 8. A process as defined in claim 5, wherein saiddried plant part contains combined amounts of 4-hydroxycinnamic acid and4-hydroxy-3-methoxycinnamic acid totaling no more than 1.5 mg/gm (dryweight).
 9. A process as defined in claim 4, wherein said plant part isobtained from an immature corn plant, Zea mays.
 10. A process as definedin claim 9, wherein said immature corn plant has been grown to a heightbetween about 45 centimeters and about 122 centimeters.
 11. A process asdefined in claim 9, wherein said immature corn plant has been grown to aheight that does not exceed between about 30 centimeters and about 45centimeters.
 12. A process as defined in claim 9, wherein said immaturecorn plant has been grown for less than ten weeks after planting.
 13. Aprocess as defined in claim 1, wherein said composition is administeredin a manner selected from the group consisting of: (1) oraladministration; (2) intranasal administration; (3) transmucosaladministration; (4) parenteral injection; (5) implant for sustainedrelease; and (6) transdermal patch.
 14. A process for promoting weightloss and/or suppressing appetite and/or enhancing mood and/or treatingat least one of fibromyalgia, sleep disorder, hyperglycemia, arthritis,stress, or substance addiction in a mammal by the administration of anamount of a composition defined as:

wherein “R¹”, is selected from the group consisting of H and OCH₃;wherein “R²” is selected from the group consisting of H and Glucose (asa glucoside) wherein “R³” is selected from the group consisting of H,OH, and OCH₃; or a phannaceutically acceptable salt thereof; and saidamount of said composition comprising a daily dosage of between about 5mcg and about 60 mg to promote weight loss and/or suppress appetiteand/or enhance mood and/or treat fibromyalgia, sleep disorder,hyperglycemia, arthritis, stress, or substance addiction in said mammal,wherein said composition is isolated and/or extracted and/or purifiedfrom at least one of (i) a leafy and/or immature plant part of one ormore monocotyledonous plants, (ii) animal tissue or (iii) chemicalsynthesis.
 15. The process as defined in claim 14, wherein said amountof said composition comprises a daily dosage of 15 mg.
 16. The processas defined in claim 14, wherein said composition is isolated and/orextracted and/or purified from the leafy and/or immature plant part ofone or more monocotyledonous plants selected from the group consistingof corn, wheat, barley, rye, oats, rice, sorghum, millet, bamboo, Job'sTears, barley-like grasses, and wild grasses.
 17. The process as definedin claim 16, wherein said leafy and/or immature plant part is dried. 18.The process as defined in claim 17, wherein said plant part is dried ata temperature in the range of between about 40° C. and about 45° C. 19.The process as defined in claim 17, wherein said dried plant partcontains phenols in total amounts greater than 17.0 mg/gm (dry weight).20. The process as defined in claim 17, wherein said dried plant partcontains combined amounts of 4-hydroxycinnamic acid and4-hydroxy-3-methoxycinnamic acid totaling no more than 1.5 mg/gm (dryweight).
 21. The process as defined in claim 16, wherein said plant partis obtained from an immature corn plant, Zea mays.
 22. The process asdefined in claim 21, wherein said immature corn plant has been grown toa height between about 45 centimeters and about 122 centimeters.
 23. Theprocess as defined in claim 21, wherein said immature corn plant hasbeen grown to a height that does not exceed between about 30 centimetersand about 45 centimeters.
 24. The process as defined in claim 21,wherein said immature corn plant has been grown for less than ten weeksafter planting.
 25. The process as defined in claim 14, wherein saidamount of said composition is administered in a manner selected from thegroup consisting of: (1) oral administration; (2) intranasaladministration; (3) transmucosal administration; (4) parenteralinjection; (5) implant for sustained release; and (6) trans dermalpatch.
 26. A process as defined in claim 4, wherein a portion of saidamount of said composition is obtained by at least one of chemicalsynthesis or purification from a natural plant or animal source.
 27. Aprocess as defined in claim 1, wherein said composition is obtained fromone or more monocotyledonous plants and standardized with a synthesizedform of said composition.
 28. A process as defined in claim 2, saidamount of said composition further enhancing mood and/or treating atleast one of fibromyalgia, sleep disorder, hyperglycemia, arthritis,stress, or substance addiction in said mammal.
 29. A process as definedin claim 14, wherein said composition is isolated and/or extractedand/or purified from the leafy and/or immature plant part of one or moremonocotyledonous plants selected from the group consisting of corn,wheat, barley, rye, oats, rice, sorghum, millet, bamboo, Job's Tears,barley-like grasses.